Cancer has been considered as a disease of the intracellular signal transconducing system or signal transduction mechanism. The most common cause of cancer is a series of defects, either in proteins, when they are mutated, or in the regulation of the quantities of the proteins in the cells such that they are over or under produced. Mutations to the cell surface receptors, which usually transduce the signals into the cells by means of tyrosine kinases, can lead to activation of the kinase in the absence of ligand, and passing of a signal which does not really exist. Alternatively, many receptor tyrosine kinases can be overexpressed on the cell surface leading to an inappropriately strong response to a weak signal.
Epidermal cell growth factors receptors (EGFR) are identified as one significant driving factor in the process for cellular growth and proliferation. The epidermal cell growth factors receptors family is composed of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4. The epidermal cell growth factors receptors are concerned in the process for most cancers, such as lung cancer, colon cancer and breast cancer. The overexpression and mutation of EGFR have been proved to be the leading risk factor for a breast cancer with poor prognosis. Besides, it has been verified that each of the above four members of the receptors family can aggregate with another member into a heterodimer, and form a signal transduction complex. Overexpression of one or more member(s) of this family in a malignant tumor will result in a synergistic signal transduction.
EGFR belongs to the protein tyrosine kinase (PTK) family. The protein tyrosine kinase is an group of enzymes which catalyze the transportation of phosphate groups from adenosine triphosphate (ATP) to the tyrosine residue located in a protein substrate. Protein tyrosine kinases function in normal cell growth. The overexpression and mutation of EGFR may cause the activation of receptors without ligands and the phosphorylation of some proteins, and then the signal for cell division is produced. As a result, EGFR may magnify the weak signal excessively by its own tyrosine-kinase action, and render the overproliferation of cells.
Specific PTK inhibitors as a potential anti-cancer therapeutic drug are of wide concern. Typical representatives of currently market available EGFR reversible inhibitors include Gefitinib, Erlotinib and Lapatinib, and inhibit the EGFR wild-type and activating mutations (e.g. Exon 19 deletion activating mutation, or L858R activating mutation). Their structures are as follows, and are respectively useful for treating non-small cell lung cancer (NSCLC) and breast cancer. Clinical study proves gefitinib and erlotinib have a favorable therapeutic effect on NSCLC patients with EGFR exon 19 deletion or L858R mutation. However, their limitations are that patients develop drug resistance after treatment, so that inhibitors of this type are limited in their further clinical applications. The study shows that 50% of resistance formed after the treatment with gefitinib and erlotinib is associated with a second mutation occurred in EGFR (T790M) (Pao W. et al., Plos Med., 2:1-11, 2005). The therapeutic effect as reversible inhibitor is lost.

T790M is located at the entrance of the ATP binding pocket of EGFR, and the size of its side chain directly affects the ability of EGFR binding to ATP. The T790M mutation spatially inhibits the interaction of the EGFR inhibitor and the ATP binding site, increases the affinity of EGFR to ATP, and makes the cells resistant to the EGFR inhibitors.
Compared to reversible EGFR inhibitors, irreversible EGFR inhibitors have very prominent advantages. Irreversible EGFR inhibitors can inhibit EGFR for a long time and are only limited by the normal rate of receptor re-binding (also called reversion). It is found that the irreversible EGFR inhibitor can covalently bind to the cysteine residue (Cys797) of the EGFR by Michael addition reaction and expand the binding sites of irreversible EGFR inhibitors and the ATP, so that the resistance caused by the T790M mutation can be overcame to some extent (Li D et al., Oncogene, 27:4702-4711, 2008). Currently market available irreversible EGFR inhibitors include BIBW-2992 (Afatinib), those in development include HKI-272 (Neratinib), EKB-569 (Pelitinib), PF00299804 (Dacomitinib) and the like, and their structures are as follows.

However, these irreversible EGFR inhibitors, which can inhibit EGFR T790M, also have a large inhibition effect on the wild-type EGFR, leading to severe side effects such as diarrhea, erythra, nausea, anorexia, and weakness (Besse, B. et al. Eur. J. Cancer Suppl., 6, 64, abstr. 203, 2008; Janne, P. A. et al., J. Clin. Oncol., 25: 3936-3944, 2007). Accordingly although it is reported in the literature that in the preclinical study, BIBW2992 (Afatinib) and PF00299804 (Dacomitinib) show a significant antitumor activity and can inhibit the activities of EGFR and EGFR T790M, however, due to the occurrence of these adverse reactions, the clinical dose and the effective blood drug concentration are limited in the clinical course. Therefore, there is no remarkable progress for BIBW2992 (Afatinib) and PF00299804 (Dacomitinib) in overcoming the T790M resistant mutation (Katakami N, Atagi S, Goto K, et al. [J]. Journal of Clinical Oncology, 2013, 31(27): 3335-3341.; Jänne P A, Boss D S, Camidge D R, et al. [J]. Clinical Cancer Research, 2011, 17(5): 1131-1139.; Landi L, Cappuzzo F. [J]. Translational Lung Cancer Research, 2013, 2(1): 40-49.).
The above-mentioned reversible or irreversible EGFR inhibitors, being currently marketed or under development, are mainly quinazoline compounds. The currently reported quinazoline EGFR inhibitors are the ATP competitive inhibitors of wild-type EGFR, leading to the occurrence of some side-reaction. In 2009, a group of pyrimidine-based irreversible EGFR inhibitors which are specific to the EGFR T790M was reported by the researchers, and the structures are shown below. Compared to the existing aniline quinazoline EGFR inhibitors, these pyrimidine-based compounds have a 30-100 fold higher inhibition activity for the EGFR T790M, and a 100 fold lower inhibition activity for the wild-type EGFR (WenjunZhou et al., Nature, 462:1070-1074, 2009). However, these pyrimidine-based compounds did not enter the clinical study later.

International Patent Application WO 2012/061299 A1 filed by Avila Therapeutics discloses another series of pyrimidine-based compounds, and the structures are shown below. The representative compound is CO1686. It is reported in the literature that CO1686 can selectively act on the EGFR activating mutation and the T790M resistant mutation, but have a weak inhibition effect on the wild-type EGFR (Walter A O, Sjin R T T, Haringsma H J, et al. [J]. Cancer discovery, 2013, 3(12): 1404-1415.). Currently, this compound is ready to enter Phase-II clinical stage.

International Patent Application WO 2013/014448 A1 filed by ASTRAZENECA AB also discloses a series of pyrimidine-based compounds, and their structures are shown below. The representative compound is AZD9291. This compound has a better inhibition effect on the EGFR activating mutation and the T790M resistant mutation than the wild-type EGFR, and is now in Phase I clinical stage.

There is an urgent demand in the current anti-tumor field to overcome the problems of the clinically common EGFR resistant mutation (e.g. T790M mutation) and the toxic and side effects of the existing EGFR inhibitors, i.e., develop more small molecule inhibitors that show a higher inhibition effect on some activating mutation and resistant mutation EGFRs and a lower inhibition effect on the wild-type EGFR. During the study of the EGFR inhibitors, the present inventors surprisingly discovered a group of pyridinylaminopyrimidine derivatives, which have a remarkably higher inhibition activity on the EGFR activating mutation (e.g. Exon 19 deletion activating mutation, or L858R activating mutation) and the T790M resistant mutation than the wild-type EGFR (WT EGFR), and has good selectivity, low toxic and side effects, and good safety. It is expected that this kind of inhibitors will have a good therapeutic effect, can overcome the problems of drug resistance and toxic/side effects, and accordingly may have good development prospects.